tbuckley/cabot-search huggingface dataset:
Abstract 2081: Poly ADP-ribose polymerase inhibition enhances T cell cytotoxicity and anti-tumor function by altering NAD+ levels
Authors: Matthew J. Dean, Liqin Zheng, Phaethon Philbrook, Augusto C. Ochoa, A. Hamid Boulares
Journal: Cancer Research (2022)

Abstract Poly ADP-ribose polymerase (PARP) is an NAD-dependent DNA repair enzyme. Inhibition of PARP in BRCA-mutant cancers has been a clinically approved therapy for several years. While the PARP inhibitor, olaparib, has been approved for the treatment of BRCA-mutant breast and ovarian cancers, it has not been used in other cancers because its mechanism of action relies on synthetic lethality. We have found that olaparib may also have use in other cancers due to its ability to modulate the immune system directly. Specifically, we have found that olaparib is able to increase the proliferation, activation, and cytotoxicity of T cells in vitro and reduce tumor growth in vivo at low doses. Recent papers have proposed that olaparib is able to enhance T cell function through the stimulator of interferon genes (STING) pathway by enhancing antigen presenting cell activity and resulting in more granzyme B expression and enhanced tumor killing. Using purified T cells from both wild type and STING knockout mice, we have shown that olaparib can also cause an increase in granzyme B and perforin expression, an increase in T cell proliferation, and enhanced tumor cell killing in a STING-independent manner. Because PARP is an NAD-consuming enzyme, we examined the role of NAD+ in the activation T cells and the production of granzyme B and perforin. By using an inhibitor of NAD+ recycling, FK866, we show that T cells have reduced NAD+ levels, reduced granzyme B and perforin expression, and even fail to activate in the presence of CD3 and CD28 when NAD+ is limited; however, adding olaparib to these cells rescues the effects of FK866 and allows proliferation and granzyme B production. In vivo we can see that even at olaparib doses that are significantly below those which induce synthetic lethality of tumor cells, olaparib is able to inhibit tumor growth in models of both colorectal and breast cancer. This suggests that olaparib can modulate the activity of T cells directly and has implications for enhancing the anti-tumor activity of these cells both alone and in combination with other forms of immunotherapy. Citation Format: Matthew J. Dean, Liqin Zheng, Phaethon Philbrook, Augusto C. Ochoa, A. Hamid Boulares. Poly ADP-ribose polymerase inhibition enhances T cell cytotoxicity and anti-tumor function by altering NAD+ levels [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2081.
Abstract 56: MSK-ACCESS Heme: A cell-free DNA next-generation sequencing assay to identify somatic alterations in patients with lymphoma
Authors: Sara E. DiNapoli, Coleman Spence, Erika Gedvilaite, Anita Bowman, Monica Diosdado, Anna Razumova, Dana Tsui, Gilles A. Salles, Connie Batlevi, Gottfried von Keudell, Ryan Ptashkin, Ahmet Zehir, Michael Berger, A Rose Brannon, Ryma Benayed, Maria Arcila
Journal: Cancer Research (2022)

Abstract Next-generation sequencing of cell-free DNA (cfDNA) can be used to noninvasively assess and monitor patients with lymphoma. Here, we describe the preliminary validation of MSK-ACCESS Heme (Memorial Sloan Kettering-Analysis of Circulating cfDNA to Examine Somatic Status), a cfDNA assay that employs unique molecular indexing and ultra-deep sequencing to detect somatic alterations in 117 genes related to hematologic malignancies. To our knowledge, this is the first report of a clinical-grade cfDNA assay developed specifically for hematologic malignancies. Overall assay performance was assessed using 53 validation samples (26 normal samples and 27 cfDNA samples with somatic variants). Initial accuracy studies showed excellent correlation with the reference next-generation sequencing method (MSK-ACCESS Solid), detecting 32/32 (100%) of expected variants with a variant allele frequency over 1%. The limit of detection was assessed using standard samples, with detection of variants down to 0.5% variant allele frequency. Results were highly concordant in both inter- and intra-assay reproducibility studies. Overall, these data indicate that MSK-ACCESS Heme is a robust cfDNA-based assay that can be used to detect variants at low frequency with high reproducibility. Future work sequencing additional samples will be performed to further assess the performance of the panel. Citation Format: Sara E. DiNapoli, Coleman Spence, Erika Gedvilaite, Anita Bowman, Monica Diosdado, Anna Razumova, Dana Tsui, Gilles A. Salles, Connie Batlevi, Gottfried von Keudell, Ryan Ptashkin, Ahmet Zehir, Michael Berger, A Rose Brannon, Ryma Benayed, Maria Arcila. MSK-ACCESS Heme: A cell-free DNA next-generation sequencing assay to identify somatic alterations in patients with lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 56.
Sonic hedgehog pathway for the treatment of inflammatory diseases: implications and opportunities for future research
Authors: Marco Palla, Luigi Scarpato, Rossella Di Trolio, Paolo Antonio Ascierto
Journal: Journal for ImmunoTherapy of Cancer (2022)

The Sonic hedgehog (Shh) signaling pathway is an essential pathway in the human body that plays an important role in embryogenesis and tissue homeostasis. Aberrant activation of this pathway has been linked to the development of different diseases, ranging from cancer to immune dysregulation and infections. Uncontrolled activation of the pathway through sporadic mutations or other mechanisms is associated with cancer development and progression in various malignancies, such as basal cell carcinoma, medulloblastoma, pancreatic cancer, breast cancer and small-cell lung carcinoma. Targeted inhibition of the pathway components has therefore emerged as an attractive and validated therapeutic strategy for the treatment of a wide range of cancers. Currently, two main components of the pathway, the smoothened receptor and the glioma-associated oncogene homolog transcriptional factors, have been investigated for the development of targeted drugs, leading to the marketing authorization of three smoothened receptor inhibitors for the treatment of basal cell carcinoma and acute myeloid leukemia. The Shh pathway also seems to be involved in regulating the immune response, possibly playing a role in immune system evasions by tumors, development of autoimmune diseases, such as rheumatoid arthritis and Crohn’s disease, airway inflammation, and diseases related to aberrant activation of T-helper 2 cellular response, such as allergy, atopic dermatitis, and asthma. Finally, the Shh pathway is involved in pathogen-mediated infection, including influenza-A and, more recently, SARS-CoV-2 viruses. Therefore, agents that inhibit the Shh signaling pathway might be used to treat pathogenic infections, shifting the therapeutic approach from strain-specific treatments to host-based strategies that target highly conserved host targets.
Abstract 4236: Temporal inhibition of BCAT1 alters metal homeostasis leading to reversal of terminal exhaustion of CD8 T cells, increased cytotoxicity, and increased efficacy of checkpoint inhibition in cancer
Authors: Adonia E. Papathanassiu, Weixing Li, Hong A. Vu
Journal: Cancer Research (2022)

Abstract We have previously demonstrated that BCAT1, the enzyme responsible for the reversible transamination of leucine in the cytosol, is a druggable target in immune-oncology: the small molecule inhibitor ERG245 dramatically increases the efficacy of anti-PD-1 treatment in the moderately immunogenic CT26 colon cancer model. We have also shown that Bcat1 gene expression is enriched in exhausted CD4+ and CD8+ intratumoral cells in cancer patients from diverse cancers. Here, we illustrate that the adoptive cell transfer (ACT) of murine CD8+ T cells treated with ERG245 increased the median survival of CT26 tumor-bearing mice from 25 days, observed with the ACT of untreated CD8+ T cells, to 32 days. This suggested that inhibition of BCAT1 prevented the known exhaustion of adoptively transferred CD8+ T cells, induced by the tumor microenvironment of CT26 tumors. To confirm this hypothesis, we developed an in vitro model of generating terminally exhausted (PD-1+TIM-3+GZMB+CXCL13+) CD8+ T cells by subjecting the cells to consecutive cycles of αCD3/αCD28 activation in the presence of TGF-β. Addition of ERG245 in the last activation cycle decreased terminal exhaustion of the cells. Mechanistically, bulk RNAseq experiments indicated and ICP analysis confirmed that inhibition of BCAT1 interfered with metal homeostasis leading to increased concentrations of Fe in the mitochondria and decreased concentrations of Zn in the nucleus of newly activated CD8+ T cells. The immediate impact of ERG245 treatment on the cells included a general decrease in the genes of processes depending on proper metal equilibrium such as cholesterol biosynthesis and ribosome biogenesis. Withdrawal of BCAT1 restored or reversed the cell phenotype leading to epigenetically altered CD8+ T cells with decreased histone acetyltransferase and histone demethylase presence, increased cytotoxicity, and increased ribosome biogenesis. Collectively, the data suggest that temporal inhibition of BCAT1 inhibition induces profound effects on CD8+ T cells including increased cytotoxicity and suppression of terminal exhaustion, thus rendering the cells rescuable by anti-PD-1 therapy. Citation Format: Adonia E. Papathanassiu, Weixing Li, Hong A. Vu. Temporal inhibition of BCAT1 alters metal homeostasis leading to reversal of terminal exhaustion of CD8 T cells, increased cytotoxicity, and increased efficacy of checkpoint inhibition in cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4236.
Abstract 2392: Adapted tumor suspension cells rewire metabolic pathways for anchorage independent survival
Authors: Young Yang, Hyun Jeong Ju
Journal: Cancer Research (2022)

Abstract Metastatic spread of cancer cells is the main cause of cancer-related death. As cancer cells adapt themselves in a suspended state in the blood stream before penetration and regrowth at distal tissues, understanding their survival strategy in an anchorage-independent condition is important to develop appropriate therapeutics. We have previously generated adapted suspension cells (ASCs) from parental adherent cancer cells to study the characteristics of circulating tumor cells. In this study, we explored metabolic rewiring in MDA-MB-468 ASCs to adapt to suspension growth conditions through extracellular flux analyses and various metabolic assays. We also determined the relationship between protein kinase B (AKT) activation and metabolic rewiring in ASCs using the AKT inhibitor, MK2206. ASCs reprogramed metabolism to enhance glycolysis and basal oxygen consumption rate. RNA-sequencing analysis revealed the upregulation in the genes related to glycolysis, tricarboxylic acid cycle, and oxidative phosphorylation. The changes in the metabolic program led to a remarkable dependency of ASCs on carbohydrates as an energy source for proliferation as compared to parental adherent cells (ADs). AKT activation was observed in ASCs and those generated from pancreatic and other breast cancer cells, and AKT activation inhibition in ASCs decreased glycolysis and oxygen consumption. AKT activation is an important strategy for obtaining energy through the enhancement of glycolysis in ASCs. The regulation of AKT activity and/or glycolysis may provide a new therapeutic strategy to prevent the metastatic spread of cancer cells. Citation Format: Young Yang, Hyun Jeong Ju. Adapted tumor suspension cells rewire metabolic pathways for anchorage independent survival [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2392.
Abstract 3238: GBP3 promotes glioblastoma resistance to temozolomide by enhancing DNA damage repair
Authors: Ming Li, Hui Xu
Journal: Cancer Research (2022)

Abstract Glioblastoma is the most common malignant brain cancer with dismal survival and prognosis. Temozolomide (TMZ) is a first-line chemotherapeutic agent for glioblastoma, but the emergence of drug resistance limits its anti-tumor activity. We previously discovered that the interferon inducible guanylate binding protein 3 (GBP3) is highly elevated and promotes tumorigenicity of glioblastoma. Here, we show that TMZ treatment significantly upregulates the expression of GBP3 and stimulator of interferon genes (STING), both of which increase TMZ-induced DNA damage repair and reduce cell apoptosis of glioblastoma cells. Mechanistically, relying on its N-terminal GTPase domain, GBP3 physically interacts with STING to stabilize STING protein levels, which in turn induces expression of p62 (Sequestosome 1), nuclear factor erythroid 2 like 2 (NFE2L2, NRF2), and O6-methlyguanine-DNA-methyltransferase (MGMT), leading to the resistance to TMZ treatment. Reducing GBP3 levels by RNA interference in glioblastoma cells markedly increases the sensitivity to TMZ treatment in vitro and in murine glioblastoma models. Clinically, GBP3 expression is high and positively correlated with STING, NRF2, p62, and MGMT expression in human glioblastoma tumors, and is associated with poor outcomes. These findings provide novel insight into TMZ resistance and suggest that GBP3 may represent a novel potential target for the treatment of glioblastoma. Citation Format: Ming Li, Hui Xu. GBP3 promotes glioblastoma resistance to temozolomide by enhancing DNA damage repair [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3238.
Abstract 2699: Glucocorticoid receptor biology in lobular breast cancer
Authors: Candace Frerich, Ishrat Durdana, Ariella Hanker, Carlos L. Arteaga, Lynda Bennett, Suzanne Conzen
Journal: Cancer Research (2022)

Abstract While considered uncommon, there are an estimated 39,000 new invasive lobular carcinoma (ILC) cases in the US yearly, making it the sixth most common among all tumor types. ILC is recognized for unique metastatic organotropism. Its propensity to metastasize to serosal surfaces lining the gut (peritoneum) and lung (pleura) make it particularly challenging to diagnose and consequently is associated with overall unfavorable prognosis. We hypothesize that GR activation will slow cell proliferation and reduce metastatic potential of ILC cells in vitro and in vivo. Using transcriptome data from 142 ILC tumors with long-term follow up clinical data from the METABRIC dataset we found a trend towards improved overall patient survival with increased GR (NR3C1) expression (and presumably activity). Preliminary in vitro data showed slowed cell proliferation in an ILC cell line (MDA-MB-134IV) treated with GR agonist dexamethasone relative to vehicle control. ILC cell lines (MDA-MB-134IV and SUM44PE) have dramatically different adhesion preference for extracellular components and we will study whether GR mediates the metastatic organotrophism of ILC cells. Preliminary transcriptome data lends insight into the proliferative and adhesive gene expression changes elicited by both ER and GR activation. Two GR+ ILC patient derived organoid lines have GR dependent proliferative and adhesive phenotypes. In future studies we will utilize an in vivo mouse model that recapitulates ILC progression from an in situ to invasive breast carcinoma and finally to metastatic colonization of distant organs to determine the role of GR activity in proliferation and metastasis to the serosal surfaces. Citation Format: Candace Frerich, Ishrat Durdana, Ariella Hanker, Carlos L. Arteaga, Lynda Bennett, Suzanne Conzen. Glucocorticoid receptor biology in lobular breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2699.
Synovial fibroblasts as potential drug targets in rheumatoid arthritis, where do we stand and where shall we go?
Authors: Tamás Németh, György Nagy, Thomas Pap
Journal: Annals of the Rheumatic Diseases (2022)

Fibroblast-like synoviocytes or synovial fibroblasts (FLS) are important cellular components of the inner layer of the joint capsule, referred to as the synovial membrane. They can be found in both layers of this synovial membrane and contribute to normal joint function by producing extracellular matrix components and lubricants. However, under inflammatory conditions like in rheumatoid arthritis (RA), they may start to proliferate, undergo phenotypical changes and become central elements in the perpetuation of inflammation through their direct and indirect destructive functions. Their importance in autoimmune joint disorders makes them attractive cellular targets, and as mesenchymal-derived cells, their inhibition may be carried out without immunosuppressive consequences. Here, we aim to give an overview of our current understanding of the target potential of these cells in RA.
Whole‐genome circulating tumor DNA methylation landscape reveals sensitive biomarkers of breast cancer
Authors: Luo Hai, Lingyu Li, Zongzhi Liu, Zhongsheng Tong, Yingli Sun
Journal: MedComm (2022)

The changes in circulating tumor DNA (ctDNA) methylation are believed to be early events in breast cancer initiation, which makes them suitable as promising biomarkers for early diagnosis. However, applying ctDNA in breast cancer early diagnosis remains highly challenging due to the contamination of background DNA from blood and low DNA methylation signals. Here, we report an improved way to extract ctDNA, reduce background contamination, and build a whole-genome bisulfite sequencing (WGBS) library from different stages of breast cancer. We first compared the DNA methylation data of 74 breast cancer patients with those of seven normal controls to screen candidate methylation CpG site biomarkers for breast cancer diagnosis. The obtained 26 candidate ctDNA methylation biomarkers produced high accuracy in breast cancer patients (area under the curve [AUC] = 0.889; sensitivity: 100%; specificity: 75%). Furthermore, we revealed potential ctDNA methylated CpG sites for detecting early-stage breast cancer (AUC = 0.783; sensitivity: 93.44%; specificity: 50%). In addition, different subtypes of breast cancer could be well distinguished by the ctDNA methylome, which was obtained through our improved ctDNA-WGBS method. Overall, we identified high specificity and sensitivity breast cancer-specific methylation CpG site biomarkers, and they will be expected to have the potential to be translated to clinical practice.
Treatment outcomes of multidrug-resistant tuberculosis with chronic kidney/liver disease
Authors: Chiwook Chung, Jung Eun Shin, Doosoo Jeon, Hyungseok Kang, Jae-Joon Yim, Kyung-Wook Jo, Tae Sun Shim
Journal: European Respiratory Journal (2022)

<b>Bedaquiline and delamanid are effective and might be safe in patients with chronic kidney or liver disease. MDR-TB patients with these comorbidities receiving bedaquiline and/or delamanid have poor treatment outcomes, probably owing to the comorbidities.</b> https://bit.ly/3NyDD15
Hybrid Closed-Loop Systems and Glycemic Outcomes in Children and Adults With Type 1 Diabetes: Real-World Evidence From a U.S.-Based Multicenter Collaborative
Authors: Nudrat Noor, Manmohan K. Kamboj, Taylor Triolo, Sarit Polsky, Ryan J. McDonough, Carla Demeterco-Berggren, Laura Jacobsen, Rona Sonabend, Osagie Ebekozien, Daniel J. DeSalvo
Journal: Diabetes Care (2022)
Assessment of Severe Maternal Morbidity and Mortality in Pregnancies Complicated by Cancer in the US
Authors: Koji Matsuo, Maximilian Klar, Ariane C. Youssefzadeh, Rachel S. Mandelbaum, Lynda D. Roman, Joseph G. Ouzounian, Jason D. Wright
Journal: JAMA Oncology (2022)

This cohort study examines nationwide trends and characteristics of severe maternal morbidity and mortality among pregnant women with cancer in the US.
Estimated incubation period for monkeypox cases confirmed in the Netherlands, May 2022
Authors: Fuminari Miura, Catharina E van Ewijk, Jantien A Backer, Maria Xiridou, Eelco Franz, Eline Op de Coul, Diederik Brandwagt, Brigitte van Cleef, Gini van Rijckevorsel, Corien Swaan, Susan van den Hof, Jacco Wallinga
Journal: Eurosurveillance (2022)

In May 2022, monkeypox outbreaks have been reported in countries not endemic for monkeypox. We estimated the monkeypox incubation period, using reported exposure and symptom-onset times for 18 cases detected and confirmed in the Netherlands up to 31 May 2022. Mean incubation period was 9.0 days* (5th–95th percentiles: 4.2–17.3), underpinning the current recommendation to monitor or isolate/quarantine case contacts for 21 days. However, as the incubation period may differ between different transmission routes, further epidemiological investigations are needed.
Normative multiple-breath washout data in school-aged children corrected for sensor error
Authors: Anne-Christianne Kentgens, Philipp Latzin, Pinelopi Anagnostopoulou, Renee Jensen, Mirjam Stahl, Alana Harper, Sophie Yammine, Rachel E. Foong, Graham L. Hall, Florian Singer, Sanja Stanojevic, Marcus A. Mall, Felix Ratjen, Kathryn A. Ramsey
Journal: European Respiratory Journal (2022)

<b>This study provides updated reference values for nitrogen multiple-breath washout outcomes in healthy, white, school-aged children in a commercially available device corrected for a known sensor error.</b>https://bit.ly/3mzBoyR
Chemistry and biological activity of resin glycosides from Convolvulaceae species
Authors: Bo‐Yi Fan, Xing Jiang, Yu‐Xin Li, Wen‐Li Wang, Min Yang, Jian‐Lin Li, An‐Dong Wang, Guang‐Tong Chen
Journal: Medicinal Research Reviews (2022)

Abstract Carbohydrate‐based drug discovery has gained more and more attention during the last few decades. Resin glycoside is a kind of novel and complex glycolipids mainly distributed in plants of the family Convolvulaceae. Over the last decade, a number of natural resin glycosides and derivatives have been isolated and identified, and exhibited a broad spectrum of biological activities, such as cytotoxic, multidrug‐resistant reversal on both microbial pathogens and mammalian cancer cells, antivirus, anticonvulsant, antidepressant, sedative, vasorelaxant, laxative, and α‐glucosidase inhibitory effects, indicating their potential as lead compounds for drug discovery. A systematic review of the literature studies was carried out to summarize the chemistry and biological activity of resin glycosides from Convolvulaceae species, based on various data sources such as PubMed, Web of Science, Scopus, and Google scholar. The keyword “Convolvulaceae” was paired with “resin glycoside,” “glycosidic acid,” “glycolipid,” or “oligosaccharide,” and the references published between 2009 and June 2021 were covered. In this article, we comprehensively reviewed the structures of 288 natural resin glycoside and derivatives newly reported in the last decade. Moreover, we summarized the biological activities and mechanisms of action of the resin glycosides with pharmaceutical potential. Taken together, great progress has been made on the chemistry and biological activity of resin glycosides from Convolvulaceae species, however, more exploratory research is still needed, especially on the mechanism of action of the biological activities.
Monkeypox in Europe and beyond – tackling a neglected disease together
Authors: Hans Kluge, Andrea Ammon
Journal: Eurosurveillance (2022)

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